CD26 is a widely distributed 110 kDa cell surface glycoprotein. CD26 was initially defined as a T-cell activation antigen (Fox et al. (1984) J. Immunol. 133, 1250-1256, Fleischer (1987) J. Immunol. 138, 1346-1350, and Morimoto et al. (1989) J. Immunol. 143, 3430-3439). This molecule has been shown to have dipeptidyl peptidase IV (DPPIV; EC3.4.14.5) activity in its extracellular domain, and wide tissue distribution (Hegen et al. (1990) J. Immunol. 144, 2908-2914 and Ulmer et al. (1990) J. Immunol. 31, 429-435). CD26 has multiple functions in human T-cell physiology. For instance, evidence suggests that CD26 can deliver a costimulatory signal for T-cell activation (Morimoto et al. (1994) Immunologist 2: 4-7 and Fleischer (1994) Immunol. Today 15: 180-184). Further, CD26 has been identified as the ADA binding protein, and the CD26/ADA complex may play a key role in regulating immune system function (Dong et al. (1996) J Immunol. 156(4):1349-55, Kameoka et al. (1993) Science. 261(5120):466-9, and Morrison et al. (1993) J Exp Med. 177(4):1135-43). A functional association between CD26 and the cellular protein topoisomerase II α has also been reported (Aytac et al. (2003) British Journal of Cancer 88:455-462).
CD26 may also have a role in development of some tumors. For instance, CD26 is expressed on the surface of some aggressive T-cell malignancies such as T-cell lymphoblastic lymphomas/acute lymphoblastic leukaemias, as well as T cell CD30+ anaplastic large cell lymphomas (Carbone et al. (1995) Blood 86(12):4617-26 and Jones et al. (2001) Am J Clin Pathol. 115(6):885-92).
A variety of murine antibodies that bind to CD26 have been reported. (See, e.g., Morimoto et al. (1989) J. Immunol. 143:3430-39, Nam Hong Dang et al. (1990) J. Immunol. 145(12):3963-71, Nam Hong Dang et al. (1990) J. Immunol. 144(11):4092-100, PCT Publication No. WO 91/07985 (Schlossman et al.), PCT Publication No. WO 02/092127 (Nam Hong Dang et al.), and U.S. Pat. No. 6,573,096 (Chen et al.).
One mouse monoclonal antibody against CD26 which has been produced is known as the 1F7 antibody. (See, e.g., U.S. Pat. No. 5,120,642, PCT Publication No. WO 91/07985 (Schlossman et al.), and Morimoto et al. (1989) J. Immunology, 143:3430-3439.) The 1F7 antibody was identified as binding to an antigen comprised of a 110,000 dalton molecular weight glycoprotein on human CD4 and CD8 lymphocytes and later identified as CD26, which was present on helper inducer cells but not suppressor inducer cells. Thus, the 1F7 monoclonal antibody has been reported as being able to distinguish between helper inducer and suppressor inducer cells in human CD4 lymphocyte populations.
In addition, the 1F7 antibody and other anti-CD26 monoclonal antibodies have been proposed to be useful in the treatment of some diseases associated with cells expressing CD26, such as some cancers. (See, e.g., U.S. Patent Publication No. 2003/0031665 and PCT Publication No. WO 02/092127 (Nam Hoang Dang et al.). Binding of the anti-CD26 monoclonal antibody 1F7 to CD26 reportedly led to cell cycle arrest at the G1/S checkpoint, and engagement of CD26 induced G1 arrest on CD26 Jurkat transfectants through enhanced expression of the cell cycle regulatory protein p21. Treatment with the 1F7 antibody has also been reported to inhibit CD26+ tumor formation and enhance survival in a mouse model (Ho et al. (2001) Clinical Cancer Research, 7:2031-2040).
Other anti-CD26 murine monoclonal antibodies that have been identified include rat anti-CD26 antibodies E19 and E26. (See, e.g., U.S. Pat. No. 6,573,096, US Patent Publication No. 2002/0132979, U.S. Patent Publication No. 2002/0132979, U.S. Patent Publication No. 2004/0115202, PCT Publication No. WO 01/74299 (Chen et al.), and Ghersi et al. (2002) J. Biological Chemistry, 32:29231-29241.) These antibodies reportedly exhibit inhibitory effects on cell migration of fibroblasts and wounded cells from a monolayer, and inhibitory effects on blood vessel tube formation, and inhibitory effect on invasion and capillary sprout formation of human dermal microvascular endothelial cells. Use of the antibodies in treatments to inhibit cancer invasion and angiogenesis has been proposed.
Another mouse anti-CD26 monoclonal antibody which has been generated is 14D10 (also referred to herein as CM03). (See, e.g., Dong et al. (1998) Mol Immunol. 35(l):13-21 and U.S. Pat. Pub. No. 2003/0031665.)
Modifying the activity of CD26 should prove helpful in treating a variety of ailments. Anti-CD26 monoclonal antibodies are one means of modifying the effects of CD26.
Murine monoclonal antibodies have been tried in human therapy. However, when murine antibodies are used therapeutically in humans, a human anti-murine antibody (“HAMA”) response develops in a significant number of treated individuals. In the HAMA response, treated subjects develop antibodies against mouse antibodies. This not only limits the effectiveness of the murine monoclonal antibody therapy, it also leads to allergic reactions which can result in anaphylaxis. In addition, even chimeric antibodies comprising human Fc regions and mouse Fv regions can potentially trigger HAMA responses.
To minimize the HAMA response, some researchers have tried to make antibodies that are not recognized as foreign by the human immune system. One method used is the “humanization” of antibodies. These humanized antibodies may contain sequences which are substantially of human origin but also generally contain some complementarity-determining region (“CDR”) residues and/or framework region residues originating from a different species, such as a rodent species, or which are purely artificial. A variety of different ways to humanize antibodies are known in the art. One form of humanization is by “grafting” antigen-specific murine complementarity-determining regions (“CDRs”) onto the framework of a human immunoglobulin molecule. Another level of humanization may include genetic engineering of murine CDR or other variable region sequences to be “more human,” thereby reducing the HAMA response. For instance, another form of humanization is by grafting the heavy and light variable chain regions from one species, such as mouse, onto human heavy and light chain constant regions and then replacing individual residues in the framework regions (“FRs”) and/or complementarity determining regions with residues derived from human antibodies and/or residues designed to lower the immunogenicity of the antibody in humans. All of these techniques may include further genetic engineering of the antibody sequences to increase the effectiveness of binding or biological effect of the antibody.
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